The Pharmacokinetics And Pharmacodynamic Study Of Gegen Qinlian Decoction In E-colil Diarrhea Mini-pigs

Objective:Explore the influence of diarrhea on the absorption of Gegen Qinlian Decoction(GQD)through pharmacokinetics(PK).Learn the change process of main pharmacological indexes through pharmacodynamic study(PD).The relationship between pharmacological index and efficacy component were studied by the results of PD and PK correlation fitting.Method:(1)Tibet minipigs aged 10-15 days were scarified for PD study of GQD after challenging with E-coli by intragastric administration.(2)The PD of TNF-? and IL-6 in plasma,white blood cell cell count in blood and E-coli count in faeces were studied.(3)A quantitative UHPLC-MS/MS method for the determination of puerarin,daidzein,daidzein,baicalin,baicalein,berberine,palmatine in pig plasma was established.The PK parameters in normal and model groups were calculated and compared.(4)The relationship between pharmacological index and efficacy component were studied by the results of PD and PK correlation fitting.(5)A quantitative UHPLC-MS/MS method for the determination of puerarin,daidzein,daidzein,baicalin,baicalein,berberine,palmatine and baicalein in fecal suspension was established.Metabolic differences of GQD between normal and model group were studied.Results:(1)The low dose GQD had better effect on anti-diarrhea,anti-inflammatory.anti-bacterial than the middle and high dose GQD,thus it was chosen as the best dosage for the following experiments.(2)After a single administration,serum IL-6,TNF-?,blood WBC and fecal E-coli counts were significantly lower than those in the model group,and the curve of each index-time were all first decline and then rise.(3)The AUCO-t and Cmax of puerarin and wogonin,the Cmax of daidzein and daidzein in the pathological group were significantly higher than those in the physiological group,while the CLz/F of baicalin was significantly reduced.The correlation analysis of PD and PK showed that there was a strong negative correlation between serum TNF-? and serum WBC and baicalin and puerarin,and a negative correlation between TNF-? and serum WBC and wogonin and jateorhizine.None of the eight ingredients but berberine showed a strong negative correlation with fecal E-coli counts.(4)Baicalin,baicalein and daidzein in GQD and pathological group were metabolized into baicalein,baicalein and daidzein respectively in the experiment of intestinal flora metabolism.The metabolites in the pathological group were the same as those in the physiological group,but the metabolic rate was two times higher than that in the physiological group.Conclusion:The uptake of puerarin and daidzein and wogonin were promoted while the eliminate of baicalin was decreased because of diarrhea,which was conducive to the efficacy of these components play a pharmacological role and had a positive impact druing the treatment of the disease.One of the reasons for the difference in pathological and physiological absorption is the acceleration metabolism of the intestinal flora on GQD in pathological group.The anti-inflammatory was mainly relied on puerarin,baicalin and baicalein in blood while the anti-bacterial effect might be relied on components in the gut which were not absorbted into blood.